Bronchial asthma is a complex, multifactorial disease characterized by reversible narrowing of the airway and hyperreactivity of the respiratory tract to external stimuli.
Identification of novel therapeutic agents for asthma is made difficult by the fact that multiple mediators are responsible for the development of the disease. Thus, it seems unlikely that eliminating the effects of a single mediator will have a substantial effect on all three components of chronic asthma. An alternative to the "mediator approach" is to regulate the activity of the cells responsible for the pathophysiology of the disease.
One such way is by elevating levels of cAMP (adenosine cyclic 3',5'-monophosphate). Cyclic AMP has been shown to be a second messenger mediating the biologic responses to a wide range of hormones, neurotransmitters and drugs; Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973!. When the appropriate agonist binds to specific cell surface receptors, adenylate cyclase is activated, which converts Mg.sup.+2 -ATP to cAMP at an accelerated rate.
Cyclic AMP modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma. As such, an elevation of cAMP would produce beneficial effects including: 1) airway smooth muscle relaxation, 2) inhibition of mast cell mediator release, 3) suppression of neutrophil degranulation, 4) inhibition of basophil degranulation, and 5) inhibition of monocyte and macrophage activation. Hence, compounds that activate adenylate cyclase or inhibit phosphodiesterase should be effective in suppressing the inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells. The principal cellular mechanism for the inactivation of cAMP is hydrolysis of the 3'-phosphodiester bond by one or more of a family of isozymes referred to as cyclic nucleotide phosphodiesterases (PDEs).
It has now been shown that a distinct cyclic nucleotide phosphodiesterase (PDE) isozyme, PDE IV, is responsible for cAMP breakdown in airway smooth muscle and inflammatory cells. Torphy, "Phosphodiesterase Isozymes: Potential Targets for Novel Anti-asthmatic Agents" in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd., 1989!. Research indicates that inhibition of this enzyme not only produces airway smooth muscle relaxation, but also suppresses degranulation of mast cells, basophils and neutrophils along with inhibiting the activation of monocytes and neutrophils. Moreover, the beneficial effects of PDE IV inhibitors are markedly potentiated when adenylate cyclase activity of target cells is elevated by appropriate hormones or autocoids, as would be the case in vivo. Thus PDE IV inhibitors would be effective in the asthmatic lung, where levels of prostaglandin E.sub.2 and prostacyclin (activators of adenylate cyclase) are elevated. Such compounds would offer a unique approach toward the pharmacotherapy of bronchial asthma and possess significant therapeutic advantages over agents currently on the market.
The compounds of this invention also inhibit the production of Tumor Necrosis Factor (TNF), a serum glycoprotein. Excessive or unregulated TNF production has been implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to human acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis, in addition to a number of autoimmune diseases, such as multiple sclerosis, autoimmune diabetes and systemic lupus erythematosis.
AIDS results from the infection of T lymphocytes with Human Immunodeficiency Virus (HIV). At least three types or strains of HIV have been identified, i.e., HIV-1, HIV-2 and HIV-3. As a consequence of HIV infection, T-cell-mediated immunity is impaired and infected individuals manifest severe opportunistic infections and/or unusual neoplasms. HIV entry into the T lymphocyte requires T lymphocyte activation. Viruses such as HIV-1 or HIV-2 infect T lymphocytes after T cell activation and such virus protein expression and/or replication is mediated or maintained by such T cell activation. Once an activated T lymphocyte is infected with HIV, the T lymphocyte must continue to be maintained in an activated state to permit HIV gene expression and/or HIV replication.
Cytokines, specifically TNF, are implicated in activated T-cell-mediated HIV protein expression and/or virus replication by playing a role in maintaining T lymphocyte activation. Therefore, interference with cytokine activity such as by inhibition of cytokine production, notably TNF, in an HIV-infected individual aids in limiting the maintenance of T cell activation, thereby reducing the progression of HIV infectivity to previously uninfected cells which results in a slowing or elimination of the progression of immune dysfunction caused by HIV infection. Monocytes, macrophages, and related cells, such as kupffer and glial cells, have also been implicated in maintenance of the HIV infection. These cells, like T cells, are targets for viral replication and the level of viral replication is dependent upon the activation state of the cells. See Rosenberg et al., The Imnmunopathogenesis of HIV Infection, Advances in Immunology, Vol. 57, 1989!. Monokines, such as TNF, have been shown to activate HIV replication in monocytes and/or macrophages See Poli et al., Proc. Nati. Acad. Sci., 87:782-784, 1990!, therefore, inhibition of monokine production or activity aids in limiting HIV progression as stated above for T cells.
TNF has also been implicated in various roles with other viral infections, such as the cytomegalovirus (CMV), influenza virus, adenovirus, and the herpes virus for similar reasons as those noted.
TNF is also associated with yeast and fungal infections. Specifically Candida albicans has been shown to induce TNF production in vitro in human moflocytes and natural killer cells. See Riipi et al., Infection and Immunity, 58(9):2750-54, 1990; and Jafari et al., Journal of Infectious Diseases, 164:389-95, 1991. See also Wasan et al., Antimicrobial Agents and Chemotherapy, 35,(10):2046-48, 1991; and Luke et al., Journal of Infectious Diseases, 162:211-214,1990!.
The ability to control the adverse effects of TNF is furthered by the use of the compounds which inhibit TNF in mammals who are in need of such use. There remains a need for compounds which are useful in treating TNF-mediated disease states which are exacerbated or caused by the excessive and/or unregulated production of TNF.
In a first aspect, this invention relates to compounds of Formula (I): ##STR1## wherein: R.sub.1 is selected from --(CR.sub.4 R.sub.5).sub.n C(O)O(CR.sub.4 R.sub.5).sub.m R.sub.6, --(CR.sub.4 R.sub.5).sub.n C(O)NR.sub.4 (CR.sub.4 R.sub.5).sub.m R.sub.6, --(CR.sub.4 R.sub.5).sub.n O(CR.sub.4 R.sub.5).sub.m R.sub.6, or --(CR.sub.4 R.sub.5).sub.r R.sub.6
wherein the alkyl moieties is unsubstituted or substituted with one or more fluorines; PA1 R.sub.4 and R.sub.5 are independently selected from hydrogen or C.sub.1-2 alky; PA1 R.sub.6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC.sub.1-3 alkyl, halo substituted aryloxyC.sub.1-3 alkyl, indanyl, indenyl, C.sub.7-11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C.sub.3-6 cycloalkyl, or a C.sub.4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl or heterocyclic moiety is unsubstituted or substituted by 1 to 3 methyl groups, one ethyl group, or an hydroxyl group; PA1 provided that: PA1 X is YR.sub.2, halogen, fluorine, NR.sub.4 R.sub.5, or formyl amine; PA1 Y is O or S(O)m'; PA1 m' is 0, 1, or 2; PA1 X.sub.2 is O or NR.sub.8 ; PA1 X.sub.3 is hydrogen or X; PA1 R.sub.2 is selected from the group consisting of --CH.sub.3 and --CH.sub.2 CH.sub.3 optionally substituted by 1 or more fluorines; PA1 R.sub.3 is COOR.sub.14, C(O)NR.sub.4 R.sub.14 or R.sub.7 ; PA1 s is 0 to 4; PA1 W is alkyl of 2 to 6 carbons, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms; PA1 Z is CR.sub.8 R.sub.8 OR.sub.14, CR.sub.8 R.sub.8 OR.sub.15, CR.sub.8 R.sub.8 SR.sub.14, CR.sub.8 R.sub.8 SR.sub.15, CR.sub.8 R.sub.8 S(O).sub.m' R.sub.7, CR.sub.8 R.sub.8 NR.sub.10 R.sub.14, CR.sub.8 R.sub.8 NR.sub.10 S(O).sub.2 NR.sub.10 R.sub.14, CR.sub.8 R.sub.8 NR.sub.10 S(O).sub.2 R.sub.7, CR.sub.8 R.sub.8 NR.sub.10 C(Y')R.sub.14, CR.sub.8 R.sub.8 NR.sub.10 C(O)OR.sub.7, CR.sub.8 R.sub.8 NR.sub.10 C(Y')NR.sub.10 R.sub.14, CR.sub.8 R.sub.8 NR.sub.10 C(NCN)NR.sub.10 R.sub.14, CR.sub.8 R.sub.8 NR.sub.10 C(CR.sub.4 NO.sub.2)NR.sub.10 R.sub.14, CR.sub.8 R.sub.8 NR.sub.10 C(NCN)SR.sub.9, CR.sub.8 R.sub.8 NR.sub.10 C(CR.sub.4 NO.sub.2)SR.sub.9, CR.sub.8 R.sub.8 NR.sub.10 C(CR.sub.4 NO.sub.2)SR.sub.9, CR.sub.8 R.sub.8 C(O)OR.sub.14,CR.sub.8 R.sub.8 C(Y')NR.sub.10 R.sub.14, CR.sub.8 R.sub.8 C(NR.sub.10)NR.sub.10 R.sub.14, CR.sub.8 R.sub.8 CN, CR.sub.8 R.sub.8 (tetrazolyI), CR.sub.8 R.sub.8 (imidazolyl), CR.sub.8 R.sub.8 (imidazolidinyl), CR.sub.8 R.sub.8 (pyrazolyl), CR.sub.8 R.sub.8 (thiazolyl), CR.sub.8 R.sub.8 (thiazolidinyl), CR.sub.8 R.sub.8 (oxazolyl), CR.sub.8 R.sub.8 (oxazolidinyl), CR.sub.8 R.sub.8 (triazolyl), CR.sub.8 R.sub.8 (isoxazoIyl), CR.sub.8 R.sub.8 (oxadiazoly), CR.sub.8 R.sub.8 (thiadiazolyl), CR.sub.8 R.sub.8 (morpholinyl), CR.sub.8 R.sub.8 (piperidinyl), CR.sub.8 R.sub.8 (piperazinyl), CR.sub.8 R.sub.8 (pyrrolyl), CR.sub.8 R.sub.8 C(NOR.sub.8)R.sub.14, CR.sub.8 R.sub.8 C(NOR .sub.14)R.sub.8, CR.sub.8 R.sub.8 NR.sub.10 C(NR.sub.10)SR.sub.9, CR.sub.8 R.sub.8 NR.sub.10 C(NR.sub.10)NR.sub.10 R.sub.14, CR.sub.8 R.sub.8 NR.sub.10 C(O)C(O)NR.sub.10 R.sub.14, or CR.sub.8 R.sub.8 NR.sub.10 C(O)C(O)OR.sub.4 ; X.sub.5 is H, R.sub.9, OR.sub.8, CN, C(O)R.sub.8, C(O)OR.sub.8, C(O)NR.sub.8 R.sub.8, or NR.sub.8 R.sub.8 ; PA1 X.sub.4 is H, R.sub.9, OR.sub.8, CN, C(O)R.sub.8, C(O)OR.sub.8, C(O)NR.sub.8 R.sub.8, or NR.sub.8 R.sub.8 ; PA1 Y' is O or S; PA1 R.sub.7 is --(CR.sub.4 R.sub.5).sub.q R.sub.12 or C.sub.1-6 alkyl wherein the R.sub.12 or C.sub.1-6 alkyl group is unsubstituted or substituted one or more times by methyl or ethyl unsubstituted or substituted by 1-3 fluorines, --F, --Br, --Cl, --NO.sub.2, --NR.sub.10 R.sub.11, --C(O)R.sub.8, --CO.sub.2 R.sub.8, --O(CH.sub.2).sub.q R.sub.8, --CN, --C(O)NR.sub.10 R.sub.11, --O(CH.sub.2).sub.q C(O)NR.sub.10 R.sub.11, --O(CH.sub.2)qC(O)R.sub.9, --NR.sub.10 C(O)NR.sub.10 R.sub.11, --NR.sub.10 C(O)R.sub.11, --NR.sub.10 C(O)OR.sub.9, --NR.sub.10 C(O)R.sub.13, --C(NR.sub.10)NR.sub.10 R.sub.11, --C(NCN)NR.sub.10 R.sub.11, --C(NCN)SR.sub.9, --NR.sub.10 C(NCN)SR.sub.9, --NR.sub.10 C(NCN)NR.sub.10 R.sub.11, --NR.sub.10 S(O).sub.2 R.sub.9, --S(O).sub.m' R.sub.9, --NR.sub.10 C(O)C(O)NR.sub.10 R.sub.11, --NR.sub.10 C(O)C(O)R.sub.10, or R.sub.13 ; PA1 q is 0, 1, or 2; PA1 R.sub.12 is R.sub.13, C.sub.3 -C.sub.7 cycloalkyl, or an unsubstituted or substituted aryl or heteroaryl group selected from the group consisting of (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl, and phenyl; PA1 R.sub.12 is selected from R.sub.13, C.sub.3-7 cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl, or phenyl; PA1 R.sub.8 is hydrogen or R.sub.9 ; PA1 R.sub.9 is C.sub.1-4 alkyl optionally substituted by one to three fluorines; PA1 R.sub.10 is OR.sub.8 or R.sub.11 ; PA1 R.sub.11 is hydrogen, or C.sub.1-4 alkyl optionally substituted by one to three fluorines; or when R.sub.10 and R.sub.11 are as NR.sub.10 R.sub.11 they may together with the nitrogen form a 5 to 7 membered ring comprised of carbon or carbon and at least one additional heteroatom selected from O, N, or S; PA1 R.sub.13 is a substituted or unsubstituted heteroaryl group selected from the group consistinguof oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, and thiadiazolyl, and where R.sub.13 is substituted on R.sub.12 or R.sub.13 the rings are connected through a carbon atom and each second R.sub.13 ring may be unsubstituted or substituted by one or two C.sub.1-2 alkyl groups unsubstituted or substituted on the methyl with 1 to 3 fluoro atoms; PA1 R.sub.14 is hydrogen or R.sub.7 ; or when R.sub.8 and R.sub.14 are as NR.sub.8 R.sub.14 they may together with the nitrogen form a 5 to 7 membered ring comprised of carbon or carbon and one or more additional heteroatoms selected from O, N, or S; PA1 R.sub.15 is C(O)R.sub.14, C(O)NR.sub.4 R.sub.14, S(O).sub.2 R.sub.7, or S(O).sub.2 NR.sub.4 R.sub.14 ; PA1 provided that: PA1 a) a decrease of excessive in vivo IL-1 or TNF levels, respectively, in a human to normal levels or below normal levels by inhibition of the in vivo release of IL-1 by all cells, including but not limited to monocytes or macrophages; PA1 b) a down regulation, at the translational or transcriptional level, of excessive in vivo IL-1 or TNF levels, respectively, in a human to normal levels or below normal levels; or PA1 c) a down regulation, by inhibition of the direct synthesis of IL-1 or TNF levels as a postranslational event. PA1 cis-3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(4-pyridylethynyl)-1-(hydroxyme thyl)cyclohexane!, and PA1 cis-3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(4-pyridylethynyl)-1-(aminometh yl)cyclohexane!.
m is 0 to 2; PA2 n is 0 to 4; PA2 r is 0 to 6; PA2 a) when R.sub.6 is hydroxyl, then m is 2; or PA2 b) when R.sub.6 is hydroxyl, then r is 2 to 6; or PA2 c) when R.sub.6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or PA2 d) when R.sub.6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is I to 6; PA2 e) when n is 1 and m is 0, then R.sub.6 is other than H in --(CR.sub.4 R.sub.5).sub.n O(CR.sub.4 R.sub.5).sub.m R.sub.6 ; PA2 (f) R.sub.7 is not C.sub.1-4 alkyl optionally substituted by one to three fluorines; or the pharmaceutically acceptable salts thereof.
This invention also relates to the pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier or diluent.
The invention also relates to a method of mediation or inhibition of the enzymatic activity (or catalytic activity) of PDE IV in mammals, including humans, which comprises administering to a mammal in need thereof an effective amount of a compound of Formula (I) as shown below.
The invention further provides a method for the treatment of allergic and inflammatory disease which comprises administering to a mammal, including humans, in need thereof, an effective amount of a compound of Formula (I).
The invention also provides a method for the treatment of asthma which comprises administering to a mammal, including humans, in need thereof, an effective amount of a compound of Formula (I).
This invention also relates to a method of inhibiting TNF production in a mammal, including humans, which method comprises administering to a mammal in need of such treatment, an effective TNF inhibiting amount of a compound of Formula (I). This method may be used for the prophylactic treatment or prevention of certain TNF mediated disease states amenable thereto.
This invention also relates to a method of treating a human afflicted with a human immunodeficiency virus (HIV), which comprises administering to such human an effective TNF inhibiting amount of a compound of Formula (I).
Compounds of Formula (I) are also useful in the treatment of additional viral infections, where such viruses are sensitive to upregulation by TNF or will elicit TNF production in vivo.
In addition, compounds of Formula (I) are also useful in treating yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TNF or will elicit TNF production in vivo.